After watching the latest McBain movie, Abe Simpson suffers a mild case of myocardial infarction. This prompts him to confess a long-hidden secret; Homer has a half-brother.

As Grampa explains, he had met a carnival floozy and prostitute before marrying Homer's mother. They had a son, and left him at the Shelbyville Orphanage. Determined to find his brother, Homer and his family go to the orphanage and find out that Abe's son was adopted by a Mr. and Mrs. Powell and named Herbert.

Herb Powell (who looks just like Homer, except with more hair and a little less gut) is the head of Powell Motors car company (in danger of being taken over by the Japanese because of otherwise poor management). He is very rich, but is quite unhappy not knowing who he is and where he comes from. He is overjoyed upon hearing of his half-brother and invites the entire Simpson family to stay at his mansion in Detroit.

Bart, Lisa, and Maggie are enthralled by Herb's wealthy lifestyle (though Marge constantly worries about spoiling her kids), and Herb decides that Homer, being an "average" American, is the perfect person to design a new car for his company, which has been losing business due to foreign car manufacturers. Herb introduces Homer to his company's design team, who soon use his lack of vehicle knowledge to try and design 'their' perfect vehicle.

When Herb asks Homer how the car design is coming along Homer can't give him a straight answer. Herb feels that Homer is not being forceful enough with his ideas, and gives Homer a pep talk. Pretty soon, Herb has invigorated Homer, who returns to the designers and begins demanding weird items like bubble domes, fins and several horns that play "La Cucaracha". While Homer becomes more a businessman, Herb spends time with Marge and the kids, becoming more of a family man like Homer. Herb's money and prestige enables the kids to enjoy life in style, but Marge is worried they may becoming spoiled.

At the unveiling of "The Homer", Herb is horrified to discover that the car is a monstrosity that costs $82,000 (significantly more when inflation adjusted for today). Herb's company folds, his mansion is sold off and he leaves regretting that he ever met his brother. As he departs on the bus he angrily remarks to Homer that he "has no brother". Lisa laments, "His life was an unbridled success... until he found out he was a Simpson". In the end of this episode, while Homer drives the family home, Bart tells him that the car he built was great. Homer became relieved that at least one person he cares about seems to like it.

"Oh Brother, Where Art Thou?" was written by Jeff Martin and directed by Wes Archer. Homer's mom, Mona Simpson and his half-brother, Herb Powell, make their first appearances on The Simpsons in the episode. Danny DeVito guest stars as Herb.